We have contributed to an intramural NIH collaboration that has cloned the MEN1 gene. We are continuing to explore its clinical and its basic implications. We have proven that it causes selected nonendocrine tumors (angiofibroma, collagenoma, and leiomyoma). We have identified an MEN1 variant in three large families with infrequent gastrinoma. We find germline mutations in 70-80% of probands with familial MEN1 or at lower prevalence in cases with sporadic MEN1. In contrast, probands with familial isolated hyperparathyroidism have rare (about 5%) MEN1 mutations. Among the MEN1-like families without MEN1 mutation, a rare family shows mutation of the p27 cylclin dependent kinase inhibitor (CDKI) gene. p27 germline mutation in MEN1 is about 1% the frequency of MEN1 mutation. We have also found rare germline mutation of p15, p18, or p21 CDKIs. We will continue to explore these and other states for germline mutations. We have also found somatic MEN1 mutation in 15 to 35% of sporadic tumors of many endocrine organs. Thus MEN1 is the gene most frequently implicated in common endocrine tumors. We found p18 CDKI in a sporadic parathyroid adenoma. We will also determine the spectrum of pathologic states that the MEN1 or the CDKI genes contribute to through mutation and other mechanisms.